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Antimicrobial Agents and Chemotherapy, November 2000, p. 2985-2990, Vol. 44, No. 11
0066-4804/00/$04.00+0

Genetic Analysis of Azole Resistance in the Darlington Strain of Candida albicans

Hiroshi Kakeya,1 Yoshitsugu Miyazaki,2 Haruko Miyazaki,2 Katherine Nyswaner,1 Brian Grimberg,1 and John E. Bennett1,*

Clinical Mycology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,1 and 2nd Department of Internal Medicine, Nagasaki University, School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8061, Japan2

Received 4 April 2000/Returned for modification 31 May 2000/Accepted 1 August 2000

High-level azole resistance in the Darlington strain of Candida albicans was investigated by gene replacement in C. albicans and expression in Saccharomyces cerevisiae. We sequenced the ERG11 gene, which encodes the sterol C14alpha -demethylase, from our copy of the Darlington strain. Both alleles contained the histidine for tyrosine substitution at position 132 (Y132H) reported in Darlington by others, but we also found a threonine-for-isoleucine substitution (I471T) not previously reported in the C. albicans ERG11. The encoded I471T change in amino acids conferred azole resistance when overexpressed alone and increased azole resistance when added to the Y132H amino acid sequence in an S. cerevisiae expression system. Replacement of one copy of ERG11 in an azole-susceptible strain of C. albicans with a single copy of the Darlington ERG11 resulted in expression of the integrated copy and a modest increase in azole resistance. The profound azole resistance of the Darlington strain is the result of multiple mutations.

* Corresponding author. Mailing address: Clinical Center, Rm. 11C304, NIH, Bethesda, MD 20892. Phone: (301) 496-3461. Fax: (301) 480-0050. E-mail: jb46y{at}nih.gov.

Antimicrobial Agents and Chemotherapy, November 2000, p. 2985-2990, Vol. 44, No. 11
0066-4804/00/$04.00+0


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